Lung cancer is the leading cancer killer in the US with 160,000 deaths and 178,000 new cases diagnosed in 1997. Our long-term goal is to develop chemoprevention strategies to prevent the progression of lung tumorigenesis in high-risk current and former smokers. This Project will focus on the agents budesonide, Polyphenon E (a green tea extract), difluoromethylornitihine (DFMO) and myo-inositol as these agents are 1) effective in the post-initiation phase of lung tumorigenesis; 2) effective in rodent lung adenocarcinoma models and 3) have a history of therapeutic or dietary use. The Project will test the hypothesis that the efficacy of these compounds in combinations during adenoma formation and progression of adenomas to dysplasias and adenocarcinomas of lung tumorigenesis in A/J mice will be greater than the efficacy of any single agent with the goal of lowering doses, and potentially harmful side effects, without decreasing efficacy. As budesonide, a glucocorticoid agonist, and (-)-epigallocatechin gallate (EGCG, the major component of Polyphenon E) are known to block activation by the AP-1 and NF-kB family of transcription factors, the levels of AP-1 and NF-kB activity in mouse lung adenocarcinomas will be determined with and without treatment with chemopreventive agents using AP-1 or NF-kB responsive reporter genes in transgenic mice. The second hypothesis that AP-1 and NF-kB inhibition is a major mechanism of lung cancer chemoprevention will be tested directly by assaying tumor formation in transgenic animals that inducibly express dominant negative mutants of c-jun (AP-1 pathway) and IkBa (NF-kB pathway) in the respiratory epithelium. Upon completion of this project we will have defined if lower doses of known chemopreventive agents, when used in combination, are less toxic and more effective than single agents and whether AP-1 and/or NF-kB blockade in the respiratory epithelium is an important mechanism for suppression of lung tumor initiation and progression.